There is convincing evidence that endogenous cannabinoids exist in both the brain and the immune system. Two G-protein coupled cannabinoid receptors have been cloned. One is found throughout the brain in high concentrations, as well as in several peripheral tissues, whereas the other is localized exclusively in the periphery. The isolation and identification of endogenous cannabinoids, such as anandamide, led to intensified efforts to understand the functional significance of endogenous cannabinoids. Manipulation of these endogenous ligands should reveal their functional role, especially as mediated through cannabinoid receptors, and lead to a better understanding of the etiology of cannabis abuse, identification of therapeutic uses of cannabinoids, and establishment of either deleterious or protective effects on the immune system. Studies on the immune system are important since they may allow for articulation of a mechanism by which endogenous cannabinoids modulate immune function. Such modulation may be of consequence among immune compromised individuals, especially AIDS patients. The recent development of SR141716A, a potent cannabinoid antagonist, serves as an exciting new probe for fulfilling these objectives. The purpose of this proposal is to establish a multidisciplinary program, consisting of six research projects and an administrative core, to define the functional role of endogenous cannabinoids. Each P.I. is an experienced researcher who will make a unique contribution. Professor Mechoulam proposes to isolate and identify other endogenous cannabinoids from tissue fractions which exhibit cannabinoid activity. Dr. Razdan will carry out a synthetic program in which he will provide novel and innovative probes to the other members of the research team. His objectives include preparation of stable and highly potent analogs of the endogenous substances and analogs of SR141716A. Dr. Martin's research group will conduct pharmacological evaluation of endogenous ligands and analogs of endogenous agonists and of the antagonist. This group also will use both tolerance development and the antagonist to explore the plasticity of the receptor and gene expression. Dr. Aceto will determine the pharmacological consequences of chronic exposure of delta9-THC and anandamide to rats and assess their dependence liability. Drs. Cabral and Kaminski propose to establish the effects of endogenous ligands on the immune system and to elucidate a natural role of cannabinoids in immune function. Dr. Kaminski has evidence that two endogenous ligands exert different effects on immune cells. Dr. Cabral hypothesizes that endogenous ligands attenuate macrophage function which could provide neuroprotection in the brain of AIDS patients. The coordination of this highly successful research team through a program project mechanism should be highly productive and fruitful.